The overall objective of the proposed project is to use microcirculatory research methods to investigate the interaction of the sympathetic nervous system and local regulatory mchanisms during hypotensive stress. Specific objectives are: 1) to clarify the role to tissue and vascular smooth muscle hypoxia in producing cardiovascular failure during severe hemorrhage, 2) to determine the effect of various therapeutic agents (alpha blockers, beta stimulators, and synthetic glucorticoids upon nutritional blood flow and tissue oxygenation during hypotensive stress, and 3) to assess the integrity of the adrenergic neuromuscular junction in low flow states. Hamsters and rats will be subjected to a prolonged period of controlled hypotension by bleeding into a reservoir to achieve a constant mean arterial pressure of 35mm Hg. Several in vivo microcirculatory preparations (hamster cheek pouch, hamster and rat cremaster muscle, and rat mesentery) will be used to directly observe the diameters of small blood vessels and to record their reponses to hemorrhage in the presence and absence of therapeutic agents. To evaluate oxygen availability to the vascular smooth muscle and parenchymal cells, microelectrodes will be used to measure oxygen tension on the walls of microvessels and in the tissue. The role of tissue hypoxia in the failure of resistance and capacitance vessels of individual vascular beds during hypotensive stress will be further evaluated by observing vascular diameters during suffusion of the preparations with physiological saline solutions of low and high oxygen content. Other indicators of blood flow in the microcirculation to be measured or calculated include microvascular pressures, capillary density, tissue pH, and capillary red cell velocity. Stimulation of the perivascular nerve supply to mesenteric blood vessels of hemorrhaged rats and normotensive controls will be used to test the integrity of sympathetic neuromuscular transmission in the presence of steroid treatment. Vascular reactivity will be tested by topical application of vasoactive agents and by electrical stimulation of the vascular smooth muscle in the presence of a selective neural blocker.